Enzalutamide (Xtandi) plus leuprolide acetate produced a significantly longer median duration of treatment suspension compared with leuprolide alone, according to data from a post hoc exploratory analysis of the phase 3 EMBARK trial (NCT02319837) presented at the 2026 American Urological Association Annual Meeting.
In the intention-to-treat (ITT) population, which included all 1068 randomized patients, the enzalutamide combination arm (n = 355) achieved a median suspension duration of 17.0 months (range, 0-109.0 months) vs 11.5 months (range, 0-110.9 months) for leuprolide alone (n = 358; P < .0001). Enzalutamide monotherapy (n = 355) produced a median suspension of 8.8 months (range, 0-105.5 months), which was not significantly different from leuprolide alone (P = .381). Treatment suspension was most likely to last at least 24 months in the enzalutamide combination group, while patients on leuprolide alone were the most likely to have no treatment suspension at all.
Key Takeaways From the Post Hoc Analysis
- Enzalutamide plus leuprolide produced a median treatment suspension of 17.0 months vs 11.5 months with leuprolide alone in the full ITT population of EMBARK (P < .0001).
- Treatment suspension was most likely to last ≥24 months in the enzalutamide combination group and <1 year in the enzalutamide monotherapy group.
- Despite longer time off treatment, enzalutamide plus leuprolide previously demonstrated superior overall survival vs leuprolide alone in the primary EMBARK analysis.
“These findings support the potential for a treatment holiday with enzalutamide combination [therapy] to maintain efficacy while reducing the treatment burden in patients with high-risk biochemically recurrent prostate cancer,” Neal D. Shore, MD, lead study author stated during the presentation.
Shore is director of research at START Carolinas/Carolina Urologic Research Center in Myrtle Beach, South Carolina.
What was the rationale for this post hoc analysis?
EMBARK enrolled patients with high-risk biochemically recurrent prostate cancer following radical prostatectomy or external-beam radiation therapy (EBRT), with a screening prostate-specific antigen (PSA) level of at least 1 ng/mL after prostatectomy or at least 2 ng/mL above the post-EBRT nadir, a PSA doubling time of 9 months or less, no evidence of metastases on conventional imaging, and a testosterone level of at least 150 ng/dL.
Patients were randomly assigned 1:1:1 to enzalutamide 160 mg orally once daily plus leuprolide acetate 22.5 mg intramuscularly every 12 weeks, placebo plus leuprolide acetate, or enzalutamide monotherapy 160 mg orally once daily. At week 37, patients with a PSA level below 0.2 ng/mL suspended treatment; those who did not achieve this threshold remained on therapy.
Previously published analyses of treatment suspension duration did not account for lower suspension rates in the control arm: 90% of patients in the enzalutamide combination arm, 86% in the enzalutamide monotherapy arm, and 67% in the leuprolide alone arm achieved treatment suspension. The current post hoc exploratory analysis used the full ITT population and assigned a suspension duration of 0 months to patients who did not suspend to ensure an unbiased comparison.
How did baseline characteristics compare across treatment arms?
Baseline characteristics were well balanced across all three arms, Shore noted. Median age was 69 years (range, 51-87) in the enzalutamide combination group, 70 years (range, 50-92) in the leuprolide alone group, and 69 years (range, 49-93) in the enzalutamide monotherapy group. Median PSA doubling time was 4.6 months, 5.0 months, and 5.0 months, respectively. Median serum PSA at screening was 5.0 ng/mL, 5.5 ng/mL, and 5.3 ng/mL across the three arms. ECOG performance status was 0 in more than 90% of patients in all groups. Primary definitive therapy was prostatectomy alone in 25.4%, 20.9%, and 27.9%; radiation therapy alone in 24.2%, 29.1%, and 25.4%; and combined prostatectomy and radiation therapy in 50.4%, 50.0%, and 46.8% of patients in the enzalutamide combination, leuprolide alone, and enzalutamide monotherapy groups, respectively.
What are the clinical implications of these findings?
“Despite nearly 6 months longer treatment suspension, [the] enzalutamide combination demonstrated superior overall survival compared with leuprolide alone,” Shore stated.2
Shore added that these data raise the possibility that treating patients with enzalutamide combination therapy may allow for longer periods off treatment without compromising efficacy outcomes.
References
- Shore ND, Sieber P, De Giorgi U, et al. Duration of treatment suspension among all randomized patients in EMBARK. Presented at: 2026 American Urological Association Annual Meeting; May 15-18, 2026; Washington, DC. Abstract PD23-05.
- Shore ND, de Almeida Cruz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. 2025; Published October 19, 2025. doi:10.1056/NEJMoa2510310
